Moderate-intensity statin plus ezetimibe: time to rethink it as an optimal initial lipid-lowering strategy

Background: Prior studies have shown an independent association between visit-to-visit variability in low-density lipoprotein cholesterol (LDL-C) and adverse cardiovascular (CV) events and that this variability can be reduced by high-intensity statins (HIS). However, it is not known whether LDL-C variability can be reduced by moderate-intensity statin (MIS) plus ezetimibe combination or by a treat-to-target strategy (TTS). Hypothesis: We aimed to evaluate whether visit-to-visit variability in LDL-C is affected by lipid-lowering strategies and its association with CV outcomes in patients treated with HIS or MIS plus ezetimibe or statins with a target LDL-C levels of 50 to 70 mg/dL (TTS). Methods: Data from the RACING and LODESTAR trial in patients with atherosclerotic disease, LDL-C variability was evaluated from 3 months after randomization. In the RACING trial, MIS plus ezetimibe combination therapy was compared with HIS monotherapy. In the LODESTAR trial, TTS with a target LDL-C level of 50 to 70 mg/dL by titration of the statin intensity was compared with HIS strategy. LDL-C variability was compared according to these lipid-lowering strategies. The primary endpoint was a composite of death, myocardial infarction, stroke, or coronary revascularization. Results: Among the 6800 patients included, when compared with patients randomized to HIS, LDL-C variability was similar in the group randomized to MIS plus ezetimibe combination (SD 8.92±7.15 vs 9.17±7.34, P=0.325) but higher in those randomized to TTS (SD 8.9±7.2 vs 10.6±7.7, P=0.001). There was a linear association between LDL-C variability and primary endpoint (Figure 1). The variability in LDL-C (by SD) was a predictor of primary endpoint (HR 1.024; 95% CI 1.014 to 1.035; P<0.001) even after adjustment for lipid-lowering strategy and mean LDL-C. Conclusions: Compared with HIS therapy, visit-to-visit variability in LDL-C was not increased in the MIS plus ezetimibe combination therapy, but was increased in the TTS. Even in those treated with MIS plus ezetimibe or HIS or statins with a target LDL-C levels of 50 to 70 mg/dL, increased LDL-C variability was significantly associated with higher risk of adverse CV outcome.

BackgroundsHigh-intensity statin is recommended for patients undergoing percutaneous coronary intervention (PCI), and ezetimibe is recommended to be added in patients not achieving low-density lipoprotein cholesterol (LDL-C) targets. Moderate-intensity statin plus ezetimibe can reduce LDL-C levels similar to high-intensity statin. The aim of this study is to examine the long-term efficacy and safety of moderate-intensity statin plus ezetimibe as the first-line strategy compared to high-intensity statin in patients undergoing PCI.MethodData was obtained from the Health Insurance Review and Assessment Service database of South Korea. Patients who underwent PCI from 2012 to 2017 were included. The primary efficacy endpoint was major adverse cardiac cerebrovascular events (MACCEs), a composite of all-cause death, revascularization, or ischemic stroke. The safety endpoint was new-onset diabetes mellitus (DM).ResultsA total of 45,501 patients received high-intensity statin (n = 38,340) or moderate-intensity statin plus ezetimibe (n = 7,161). Among propensity-score-matched 7,161 pairs, MACCEs occurred in 1,460 patients with high-intensity statin and 1,406 patients with moderate-intensity statin plus ezetimibe (33.8% vs. 31.9%, hazard ratio 0.96, 95% confidence interval 0.89–1.03, P = 0.27) at a median follow-up of 2.7 years. DM was newly diagnosed in 398 patients with high-intensity statin and 342 patients with moderate-intensity statin plus ezetimibe (12.5% vs. 10.7%; hazard ratio 0.84, 95% confidence interval 0.73–0.97, P = 0.02).ConclusionIn patients undergoing PCI, moderate-intensity statin plus ezetimibe demonstrated a similar risk of MACCEs but a lower risk of new-onset DM than high-intensity statin. Early combination treatment of moderate-intensity statin and ezetimibe may be a useful and safe lipid-lowering strategy after PCI.Graphical abstractCumulative incidence according to the first-line lipid-lowering strategy in patients undergoing percutaneous coronary intervention. Abbreviation: MACCE, major adverse cardiac cerebrovascular events; PCI, percutaneous coronary intervention.

Achievement of low-density lipoprotein cholesterol (LDL-C) targets is crucial for the prevention of cardiovascular disease (CVD) in individuals with dyslipidaemia who are at high risk. Current guidelines recommend high-intensity statins at the highest tolerated dose as initial treatment to achieve LDL-C goals. However, the real-world situation is dismal: high-intensity statins are underused and achievement of LDL-C goals is suboptimal. Various challenges exist in the implementation of the recommended initial treatment strategy, including hesitancy to use high-intensity statins, non-adherence, and side effects, and the response to high-intensity statins varies across individuals. Emerging studies have shown another line of lipid-lowering, moderate-intensity statins in combination with ezetimibe, presenting considerable efficacy/effectiveness, along with better safety and adherence compared to statin intensification alone. Here we review the clinical evidence, treatment guidelines and challenges associated with high-intensity statins, and summarise the evidence on the combination therapy, moderate-intensity statin plus ezetimibe, which is the core strategy recommended by the 2023 Chinese Guideline for Lipid Management, as a possible primary treatment to achieve the LDL-C targets across several populations. The upfront use of a moderate-intensity statin plus ezetimibe may improve LDL-C control and lead to the prevention of CVD in real-world settings.

PurposeWe aimed to compare the visit-to-visit variability in low-density lipoprotein cholesterol (LDL-C) according to different lipid-lowering strategies and evaluate its prognostic implications using data from previous trials.Materials and MethodsWe analyzed two randomized clinical trials: the RACING trial and the LODESTAR trial. LDL-C variability was evaluated using standard deviation (SD), coefficient of variation, and variation independent of mean. The primary endpoint was a composite of death, myocardial infarction, stroke, or coronary revascularization.ResultsAmong the 6800 patients included, when compared with patients randomized to high-intensity statins, LDL-C variability was similar in the group randomized to moderate-intensity statin plus ezetimibe combination, but it was higher in those randomized to treat-to-target strategy. The variability in LDL-C (by SD) was a predictor of primary endpoint even after adjustment for lipid-lowering strategy and mean LDL-C (hazard ratio 1.024; 95% confidence interval 1.014 to 1.035; p<0.001). Every 1-SD increase in LDL-C variability (SD) was also independently associated with higher risk of myocardial infarction by 2.1%, stroke by 3.5%, and coronary revascularization by 2.7%.ConclusionCompared to high-intensity statin therapy, LDL-C variability was not increased with the moderate-intensity statin plus ezetimibe combination therapy; however, it was increased in the treat-to-target strategy. Even among those treated with moderate- or high-intensity statins or statins with a target LDL-C levels of 50–70 mg/dL, increased LDL-C variability was associated with higher risk of adverse cardiovascular outcomes.

Studies comparing the clinical efficacy and safety of intensive statin therapy with ezetimibe-statin combination therapy are still rare at present, especially in Asian population. We enrolled 202 patients who suffered acute coronary syndrome (ACS) and underwent percutaneous coronary intervention (PCI) between May and July in 2016. Patients were allocated into three groups based on the lipid lowering strategy: moderate-intensity statin group (n=118), ezetimibe combined with moderate-intensity statin group (ezetimibe-statin combination, n=55) and intensive statin group (n=29). The lipid profiles and side effects were analyzed and compared among the patients in three groups at admission, 1 month and 3 months after PCI. The clinical outcomes of the patients were observed through 6-month follow-up. One month after PCI, the level of non-high density lipoprotein-cholesterol (non-HDL-C) was decreased by 41.9%, 21.6% and 29.8% by ezetimibe-statin combination therapy, moderate-intensity statin therapy and intensive statin therapy, respectively (P<0.05). The reduction percentages of TC and LDL-C were significantly higher in ezetimibe-statin combination group than in moderate-intensity statin group (P<0.001). The proportion of patients reaching LDL-C goal was higher in ezetimibe-statin combination group (69.1%, P=0.007) and intensive statin group (67.9%, P=0.047) compared with moderate-intensity statin group (46.9%) at 1 month after PCI. There was no significant difference among the three groups with respect to hepatic enzymes level, creatine kinase (CK) level and incidence of muscle symptoms. The reduction percentage of non-HDL-C was larger in ezetimibe-statin combination group than intensive statin group. This finding suggested that statin/ezetimibe combination therapy could be an alternative to intensive statin therapy in Chinese patients with atherosclerotic cardiovascular disease.

Cost-Effectiveness of Lipid-Lowering Treatments in Young Adults

Atherosclerotic cardiovascular disease (ASCVD) is highly prevalent in the elderly and often requires intensive lipid-lowering therapy.However, high-intensity statins may lead to adverse effects such as myopathy, liver enzyme elevations, or cognitive changes in older adults. The objective of this study was to evaluate the safety and efficacy of moderate-intensity statin therapy in combination with ezetimibe for lipid control and cardiovascular risk reduction in elderly patients with established ASCVD. This retrospective, observational cohort study was conducted at Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom, from January 2023 to June 2023. A total of 221 elderly patients (age ≥60 years) with established ASCVD were included in the study. Results: The mean low-density lipoprotein cholesterol (LDL-C) level significantly decreased from 129.4 ± 18.7 mg/dL at baseline to 78.2 ± 16.4 mg/dL at six months (p < 0.001), representing a 39.6% reduction. LDL-C <70 mg/dL was achieved in 153 patients (69.2%), and <100 mg/dL in 202 patients (91.4%). Adverse events were infrequent: myalgia occurred in seven patients (3.2%), elevated liver enzymes in five patients (2.3%), and creatine kinase increase in four patients (1.8%), with no cases of rhabdomyolysis. Medication adherence was high, with 215 patients (97.3%) remaining on therapy, and only three patients (1.4%) discontinued treatment due to adverse effects. A total of 11 patients (5.0%) experienced major adverse cardiovascular events (MACE) during follow-up. Combining moderate-intensity statins with ezetimibe is an effective and safe lipid-lowering strategy for elderly patients with ASCVD. The regimen achieved high rates of LDL-C goal attainment with minimal side effects and good adherence, making it a practical alternative to high-intensity statin monotherapy in this population.

IntroductionThe ‘strike early and strike strong’ lipid-lowering strategy emphasises rapid reduction of low-density lipoprotein cholesterol (LDL-C) in patients with acute coronary syndrome (ACS). Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) are increasingly used alongside statins to achieve guideline-recommended LDL-C targets after ACS. However, despite substantial LDL-C reductions with early PCSK9i initiation, their effects on non-culprit coronary atherosclerotic plaques remain unclear. This study aims to assess the impact of early intensive LDL-C lowering with PCSK9i added to moderate-intensity statin therapy on optical coherence tomography (OCT)-derived plaque characteristics in non-culprit coronary lesions in patients with ACS.Methods and analysisIn this prospective, multicentre, open-label trial, 212 patients with ACS will be randomised 1:1 to an early intensified lipid-lowering strategy (PCSK9i added to moderate-intensity statin) or guideline-directed medical therapy for 6 months. Serial OCT imaging of non-culprit coronary arteries with 20–70% stenosis will be performed at baseline and 6 months. The primary endpoint is the absolute change in minimum fibrous cap thickness within a matched target arterial segment from baseline to 6 months. Secondary endpoints include changes in minimum lumen area, maximum lipid arc, presence of macrophage infiltration, LDL-C reduction and achievement of LDL-C targets. The primary endpoint will be analysed using analysis of covariance, adjusting for treatment group, baseline LDL-C stratification (≥1.8 vs <1.8 mmol/L), and baseline minimum FCT. Secondary continuous outcomes will be analysed similarly, while categorical outcomes will be compared using chi-square, Fisher’s exact test or logistic regression, as appropriate.Ethics and disseminationEthics approval was granted by the Biomedical Research Ethics Committee of West China Hospital of Sichuan University (2024 Review No 1943). Results will be disseminated via peer-reviewed publications and presentations at academic conferences.Trial registration numberNCT06791031.

Atherosclerotic Cardiovascular Disease in Women: Providing Protection With Lipid-altering Agents